1. Field of the Invention.
The present invention is broadly concerned with improved, release-extending compositions for encapsulation of bioactive agents, which compositions exhibit reduced release rates of bioactive agents when compared with conventional encapsulated formulations. More particularly, the compositions of the invention include respective quantities of native, undenatured starch and biodegradable synthetic polymer wherein the polymer coats at least a portion of the starch surface area, with a quantity of bioactive agent interspersed within the admixture.
2. Description of the Prior Art.
The controlled release of any bioactive ingredient, whether pesticide, drug or fertilizer, facilitates safe and effective use. Controlled-release technology focuses on the need for the application of an active compound to a system to accomplish a specific purpose while avoiding ineffective underdosing or toxicity from overdosing. Ideally, the active agent is released at a controlled rate and maintains its concentration in the system within optimum limits for an extended period. Thus, much less of the active ingredient is required for the same period of activity than in conventional methods of administration.
When applied by conventional methods, pesticides are invariably subject to leaching, evaporation, and degradation (photolytic, hydrolytic, and microbial), all of which remove the active ingredients from their site of action before they can perform their function. In most cases following application, the rate of degradation follows first order kinetics. See, Lewis and Cowsar, "Principles of Controlled Release Pesticides", H. B. Scher, Ed., Controlled Release Pesticides (ACS Symp. Ser. 53), Am. Chem. Soc., Washington, DC, p11, 1977. Thus, if M.sub.e is the minimum effective level, M.sub.0 the amount of agent to be released during conventional methods of administration, and k.sub.r the release rate constant, then t.sub.e, the time during which an effective level of active agent is present after a single application, would be: ##EQU1##
It follows from the above equation that, to increase the duration of the effective action of a conventionally applied pesticide, the application of an exponentially greater quantity of the active agent is required. On the other hand, if the minimum effective level of active ingredient required is supplied by means of a controlled-release formulation, then the optimum amount of the active agent would be released and the duration of action would be: ##EQU2## where K.sub.d is the rate constant for active agent delivery from a controlled-release device and M.sub..infin. is the total amount of active agent encapsulated in the device. See, Zeoli and Kydomieus, "An Overview of Controlled Release Technology", Bioengineering Aspects, p63, 1983.
In the past, however, attempts to affect the controlled release of bioactive ingredients from controlled-release devices have suffered several disadvantages. In agricultural applications employing pure starch as the release device, the release rate of the pesticide is often too rapid because of biological attack of the starch matrix following field application. As a result, dangerously high levels of pesticide can develop in rain run-off from fields, which can lead to contamination of water sources used for human consumption. In some cases, the pesticide formulation will float and merely contributes to ever higher pesticide levels in the rain fun-off from fields.
The cost of processing the controlled-release device or composition is often substantially higher than that associated with standard release formulations. By way of example, injection-molding techniques to processing unmodified starch with other unknown excipients into capsules (CAPILL.TM.) includes processing steps involving cycle time, screw speed, and critical temperature control, together with expensive injection-molding equipment. Various approaches to the controlled release of chemical agents by means of a starch-based encapsulating material had been disclosed previously. Some of these approaches have involved the use of chemical crosslinking reactions and chemical bonding between the encapsulating materials. In U.S. Pat. No. 4,911,952, Doane discloses a system for encapsulation of chemical biological agents in a cooked starch system without the use of chemical crosslinking reagents. The system encapsulates the agent exclusively with starch which has been blended into an aqueous dispersion at an elevated temperature to permit reassociation with amylose molecules upon cooling of the starch/agent mixture. The result is that the reassociation forms a starch matrix entrapping discontinuous domains of the agent within the starch interstices of the reassociated starch chains. This system, however, suffers a disadvantage in that when exposed to aerobic environments or to organisms such as algae and fungi, typically found in the soil and water in agricultural settings, the reassociated starch matrix may undergo rapid degradation resulting in an undesirably high rate of release of the encapsulated agent. In agricultural settings, rapid release rates of the agents can lead to soil and ground water contamination problems.
In U.S. Pat. No. 4,282,207, Young et al. disclose a method and composition for the controlled release of pesticides by using a mixture comprising (a) a carbinol-containing organic polymer, (b) a crosslinking agent for the polymer consisting essentially of a hydrolyzable silane or organopolysiloxane containing hydrolyzable silane groups or partial hydrolyzates thereof, and (c) a pesticide. The method and composition calls for the crosslinking reaction between hydroxyl groups associated with the carbinol-containing organic polymer and either the hydrolyzable silane groups.
Some devices used to produce controlled release of bioactive agents create an adverse environmental impact, not only because of the presence of the device itself in the environment, but also because of the presence of device degradation products in the environment resulting from heat, hydrolysis, oxidation, solar radiation, and biological degradation.
Accordingly, the requirements for a successful slow-release composition for the encapsulation of bioactive ingredients are exceedingly stringent, with the most troublesome difficulty being excessively rapid release of the active ingredient following application.
The slow-release device itself, together with the degradation products of the release device (following heat, hydrolysis, oxidation, solar radiation, and biological degradation), can create an adverse environmental impact.